Minireview: Effects of Different HT Formulations on Cognition

Evidence from preclinical studies, randomized clinical trials (RCT), and observational studies underscores the importance of distinguishing among the different forms of estrogen and progestogens when evaluating the cognitive effects of hormone therapy (HT) in women. Despite this evidence, there is a lack of direct comparisons of different HT regimens. To provide insights into the effects of different HT formulations on cognition, this minireview focuses on RCT of verbal memory because evidence indicates that HT affects this cognitive domain more than others and because declines in verbal memory predict later development of Alzheimer's disease. Some observational studies indicate that estradiol confers benefits to verbal memory, whereas conjugated equine estrogens (CEE) confer risks. RCT to date show no negative impact of CEE on verbal memory, including the Women's Health Initiative Study of Cognitive Aging. Similarly, the Women's Health Initiative Memory Study showed no negative impact of CEE on dementia. Transdermal estradiol in younger postmenopausal women improved verbal memory in one small RCT but had no effect in another RCT. RCT of oral estradiol in younger and older postmenopausal women had neutral effects on cognitive function. In contrast, RCT show a negative impact of CEE plus medroxyprogesterone acetate on verbal memory in younger and older postmenopausal women. Small RCT show neutral or beneficial effects of other progestins on memory. Overall, RCT indicate that type of progestogen is a more important determinant of the effects of HT on memory than type of estrogen.